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Dendritic Cell Maturation Transcription Factor E2F1 Suppresses Transcription Factor E2F1 Suppresses Dendritic Cell Maturation Fang Fang, Yan Wang, Rui Li, Ying Zhao, Yang Guo, Ming Jiang, Jie Sun, Yang Ma, Zijia Ren, Zhigang Tian, Feng This information is current as Wei, De Yang and Weihua Xiao of September 29, 2021. J Immunol 2010; 184:6084-6091; Prepublished online 26 April 2010; doi: 10.4049/jimmunol.0902561 http://www.jimmunol.org/content/184/11/6084 Downloaded from References This article cites 40 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/184/11/6084.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Transcription Factor E2F1 Suppresses Dendritic Cell Maturation Fang Fang,*,1 Yan Wang,*,1 Rui Li,* Ying Zhao,* Yang Guo,* Ming Jiang,* Jie Sun,* Yang Ma,* Zijia Ren,* Zhigang Tian,* Feng Wei,† De Yang,†,‡ and Weihua Xiao* Transcription factor E2F1 has been largely studied as a promoter of S-phase transition in the cell cycle and as a regulator of ap- optosis. Recently, E2F1 has been shown to regulate a wide range of genes in response to inflammatory stimulation of macrophages and to contribute to T cell activation in response to pathogens, implicating an extensive immunological role for E2F1. Dendritic cells (DCs) play critical roles as professional APCs in the development of immune responses. However, it is unclear whether E2F1 has any effect on DC phenotype or function. In this paper, we report that E2F1 acts as a suppressor of DC maturation. The level of E2F1 expression was transiently downregulated in the course of LPS-induced maturation of both human monocyte-derived DCs and Downloaded from a mouse DC cell line, DC2.4. Knockdown of E2F1 by small interfering RNA in DC2.4 cells resulted in both phenotypic and functional maturation, even without LPS treatment. Conversely, ectopic overexpression of E2F1 suppressed LPS-induced maturation of DC2.4 cells. Furthermore, knockdown of E2F1 caused the activation of several major signaling pathways known to be activated in the course of DC maturation, including Erk1/2, NF-kB, and PI3K/Akt, suggesting that E2F1 may be involved in regulating multiple signaling pathways in DCs. Finally, the alteration of phenotypic maturation by E2F1 was confirmed with bone marrow-derived DCs from E2F1 knockout mice. Overall, our data demonstrate for the first time that E2F1 is a critical regulator of DC http://www.jimmunol.org/ maturation. The Journal of Immunology, 2010, 184: 6084–6091. endritic cells (DCs) are the most potent professional APCs maturation involve the upregulation of surface costimulatory (e.g., that control immunity (1). Under steady state, immature CD80 and CD86) and MHC (class I and class II) molecules, the D DCs populate peripheral tissues where they continuously activation of lysosomal Ag-processing mechanisms, the production sample the environment by endocytosis. Upon encountering of numerous immunostimulatory cytokines, and the acquisition of pathogens and/or proinflammatory mediators, DCs undergo a com- the capacity to migrate to secondary lymphoid organs (1–3). Upon plex transformation process termed “maturation,” which greatly arriving at the secondary lymphoid organs, mature DCs present by guest on September 29, 2021 enhances their Ag-presenting capacity. The general features of DC antigenic peptides displayed on their surfaces in the context of MHC molecules to naive T cells for the initiation of Ag-specific T cell *Hefei National Laboratory for Physical Sciences at Microscale and School of Life immune responses, which is a unique capacity that only mature DCs Sciences, University of Science and Technology of China, Hefei, China; possess. Therefore, controlling the maturation of DCs is critical for † Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, the regulation of adaptive immune responses. Center for Cancer Research, National Cancer Institute, Frederick, MD 21701; and ‡Basic Science Program, Science Applications International Corporation-Frederick, DC maturation can be triggered by either exogenous agents, such National Cancer Institute at Frederick, Frederick, MD 21702 as pathogen-associated molecular patterns (e.g., microbial DNA, 1F.F. and Y.W. contributed equally to this work. RNA, LPS, etc.), or endogenous mediators, such as proinflammatory Received for publication August 7, 2009. Accepted for publication March 19, 2010. cytokines (e.g., TNF, IL-1, and IFN), CD40L, and alarmins. Most This work was supported by grants from the National Natural Science Foundation of pathogen-associated molecular patterns and alarmins induce DC China (30721002 and 30528020), National Basic Research Program of China (973 maturation by triggering certain pattern-recognition receptors, such Program) (2007CB914503), Ministry of Science and Technology of China (KSCX1- as TLRs (1, 4–7). Proinflammatory cytokines stimulate DC matu- YW-R-58 and KSCX2-YW-R-174), and China Ministry of Education (20060358019). Funding to pay the open access publication charges for this article was provided ration by signaling through their specific receptors, whereas CD40L by a grant from the National Basic Research Program of China (2007CB914503; to does so by interacting with CD40, a member of the TNFR super- W.X.). This research has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01- family on the DC surface (1, 2, 7–10). Despite utilization of a variety CO-12400. This research was supported in part by the Intramural Research Program of receptors, DC maturation in response to various ligands seems to of the National Institutes of Health, National Cancer Institute, Center for Cancer stem from the activation of a number of intracellular signaling Research. pathways including NF-kB, PI3K, and multiple MAPKs, which are The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, com- collectively responsible for inducing the phenotypic and functional mercial products, or organizations imply endorsement by the U.S. Government. characteristics typical of mature DCs (2, 3, 7–9, 11, 12). NF-kBisthe Address correspondence and reprint requests to Dr. Weihua Xiao, Institute of Immu- most frequently documented transcriptional factor, which plays nology, School of Life Sciences, University of Science and Technology of China, 443 critical roles in DC maturation (7, 10–13). Silencing RelB in DCs Huangshan Road, Hefei, China 230027, or Dr. De Yang, Basic Science Program, Science Applications International Corporation-Frederick, National Cancer Insti- using small interfering RNA (siRNA) has been found to not only tute at Frederick, Frederick, MD 21702. E-mail addresses: [email protected] or inhibit DC maturation but also downregulate DC-dependent de- [email protected] velopment of Ag-specific immune responses (13). Alymphoplasia Abbreviations used in this paper: Aly, alymphoplasia; ASK1, apoptosis signal-regu- (Aly) mouse has a loss-of-function point mutant in the NF-kB– lating kinase 1; DC, dendritic cell; KO, knockout; MDC, macrophage-derived che- mokine; pcDNA, plasmid cDNA; siRNA, small interfering RNA; SLC, secondary inducing kinase (14), and consequently, all cells in Aly mice, in- lymphoid-tissue chemokine; [3H]TdR, [3H]thymidine deoxyribose; WT, wild-type. cluding DCs, are deficient in the activation of NF-kB via the www.jimmunol.org/cgi/doi/10.4049/jimmunol.0902561 The Journal of Immunology 6085 noncanonical pathway (15). DCs of Aly mice show some deficiency presence of GM-CSF and IL-4 as described previously (29). Briefly, mon- 5 in maturation and are unable to present exogenous Ags to naive CD8 ocytes were incubated at 5 3 10 /ml in RPMI 1640 medium (RPMI 1640 T cells (15). Only sporadic reports are available with respect to the plus 2 mM glutamine, 25 mM HEPES, 100 U/ml penicillin, and 100 mg/ml streptomycin) containing 10% FBS (Haidmannweg 9; PAA Laboratories, participation of other transcriptional factors in the course of DC Pasching, Austria), 50 ng/ml recombinant human GM-CSF (PeproTech, maturation, such as CREB, activating transcription factor-2, and AP- Rocky Hill, NJ), and 50 ng/ml recombinant human IL-4 (PeproTech) at 1 (10, 11). 37˚C in a CO2 (5%) incubator for 5 d. The cultures were fed with the same Transcription factor E2F1 plays divergent roles in regulating gene cytokine-containing medium every 2–3 d. To induce DC maturation, DCs were cultured in the same cytokine mixtures in the presence of LPS (100 ng/ transcription, the cell cycle, and apoptosis (16). E2F1 induces cell ml) for an indicated period of time at 37˚C in a CO2 (5%)
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